Method and composition for treating skin wounds with epidermal growth factor

ABSTRACT

Epidermal growth factor (EGF) produced by an excretory recombinant approach was tested for its efficacy in treating various skin wounds. In a randomized double blind controlled study, local cream samples prepared with human EGF at a final concentration of as low as 0.02% (g/g) in topically suitable carrier were found to have an enhancing effect on the recovery of diabetes foot ulcers. This promotional effect is statistically significant and has resulted in a reduced mean healing time of over 3 weeks when compared with that of control. Both the 0.02% (g/g) and 0.04% (g/g) human EGF supplemented samples in comparison with control showed a trend of stimulatory effect when a recovery of 50% of an ulcer was considered. The EGF samples were also shown to be highly effective in promoting treatments of wounds resulting from bedsores and surgeries.

This is a nationalization of PCT/CN03/00178 filed Mar. 11, 2003 andpublished in English which in turn is based on provisional ApplicationNo. 60/363,095 filed Mar. 12, 2002.

FIELD OF THE INVENTION

This invention relates to methods and compositions for treating skinwounds using epidermal growth factor (EGF).

BACKGROUND OF THE INVENTION

The ability of EGF to accelerate the metabolism of epithelial cells andits stimulatory effect on the healing of wounds such as skin and gastriculcers, burns and corneal injuries suggested its potential applicationto the treatment of diabetes foot ulcer. However, while EGF has beenshown to promote healing of corneal and burn wounds at a concentrationof 10 μg/ml, EGF failed to promote epithelization in wounds of patientssuffering from venous stasis ulcers at the same concentration.

Diabetic foot ulcer is a major complication of diabetes mellitus. Peoplewith diabetes mellitus may have a five to fifteen times higher risk ofnon-traumatic amputation compared with non-diabetes. Between 1996-1998diabetic patients accounted for 47% of all the lower limb amputationsperformed in a local Hong Kong hospital. In general, although somepatients can be healed with traditional methods, diabetic foot ulcerscan be difficult to heal in some patients and frequently lead toamputation if complicated by infection and gangrene. Several newtreatment modalities such as an oxygen chamber, platelet derived growthfactor (PDGF), and various local dressings have reported various degreeof success. The efficacy of such methods may be relatively low, withsome of such methods requiring at least 6 months for healing.

Besides diabetic foot ulcer, bedsores and large/deep surgical wounds maybe difficult to heal even under medication, probably resulting from thelarge areas involved. If these wounds are not treated in time, they willdeteriorate and subsequently may become incurable and life threatening.Therefore, an effective medical treatment may not only help the patientsrecover from these skin complications, but may also lead them to abetter quality of life, reduced medical care or expense, or even aprolonged life span. Unfortunately, current treatment methods may not beable to provide a relatively effective method to such large-area wounds.

OBJECT OF THE INVENTION

Therefore, it is an object of this invention to resolve at least one ormore of the problem as set forth in the prior art. As a minimum, it isan object of this invention to provide the public with a useful choice.

SUMMARY THE INVENTION

Accordingly, this invention provides, in the broad sense, a method andthe corresponding composition for treating skin wounds using EGF as theactive ingredient.

In one aspect of this invention, a method for treating skin wounds isprovided, which comprises the step of topically administering acomposition to the skin wounds, said composition including a topicallyeffective amount of epidermal growth factor (EGF) and a topicalacceptable carrier.

Another aspect of this invention provides a composition for treatingskin wounds including a topically effective amount of epidermal growthfactor (EGF) and a topical acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWING

Preferred embodiments of the present invention will now be explained byway of example and with reference to the accompany drawings in which:

FIG. 1 shows the mean healing times (100% healing) expressed in survivalfunction plots of Groups 1-3 patients being treated by the compositionsof this invention containing different amounts of EGF.

FIG. 2 shows the mean healing times (50%) expressed in survival functionplots of Groups 1-3 patients being treated by the compositions of thisinvention containing different amounts of EGF.

FIG. 3 shows the photo of the wound of Patient A before treatment.

FIG. 4 shows the photo of the wound of Patient A 2 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 5 shows the photo of the wound of Patient A 3 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 6 shows the photo of the wound of Patient B before treatment.

FIG. 7 shows the photo of the wound of Patient B 3 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 8 shows the photo of the wound of Patient B 5 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 9 shows the photo of the wound of Patient B 9 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 10 shows the photo of the wound of Patient C before treatment.

FIG. 11 shows the photo of the wound of Patient C 4 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 12 shows the photo of the wound of Patient C 6 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 13 shows the photo of the wound of Patient D before treatment.

FIG. 14 shows the photo of the wound of Patient D 2 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 15 shows the photo of the wound of Patient D 4 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 16 shows the photo of the wound of Patient B before treatment

FIG. 17 shows the photo of the wound of Patient E 5 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 18 shows the photo of the wound of Patient B 9 weeks after beingtreated with the composition of this invention having 0.04% (g/g) ofEGF.

FIG. 19 shows the mean healing times (100% healing) expressed insurvival function plots of Group 4 patients being treated by thecompositions of this invention containing 0.03% (g/g) EGF and comparingwith Groups 1 and 2 patients.

DETAIL DESCRIPTION OF PREFERRED EMBODIMENTS

This invention is now described by ways of example with reference to thefigures in the following sections.

This invention relates to the application of a composition containing atleast 0.02% (g/g) EGF and a topically acceptable carrier to the skinwound of a patient which resulted in unexpected positive healingeffects. At the very least, the time required for 50% healing, in whichthe area of the shin wound is reduced by 50%, is substantially reducedcompared with existing methods. The study of this invention found thatusing a composition containing 0.02% (g/g) or 0.04% (g/g) of EGF mayreduce the time required to achieve 50% healing by 2-4 weeks. In thecase of treating burns, it was found that even 0.001% (g) of EGF may beeffective in accelerating wound healing.

Although using 0.02% (g/g) EGF in the composition of this invention wasfound to be effective in achieving 50% healing, it was also found thatit may fail to achieve totally healing in some cases. On the other hand,when EGF is used in an amount of 0.04% (g/g), totally healing wasobserved in some patients after 4 weeks of treatment, and all of thepatients were totally healed after 12 weeks. It was also found that whenEGF is used in an amount of 0.03% (g/g), the results are almostindistinguishable from those using 0.04% (g/g) of EGF. Further detailswill be described in the following examples.

In one embodiment of this invention, the patient may first be with thecomposition containing 0.02% (g/g) EGF to achieve 50% healing, and thentreated with the composition containing 0.04% (g/g) EGF to achieve totalhealing. Although this may be more economical than using 0.04% (g/g) EGFalone as less amount of EGF may be required, the complication may beless preferred in some cases.

Naturally, human EGF (hEGF) is preferred to be used in the method andcomposition of this invention when treating human. The structure of hEGFis well documented and can at least be found in “Epidermal Growth Factorand Transforming Growth Factor alpha (by King et al in: Physiology,Biochemistry, and Molecular Biology of the Skin, L. A. Goldsmith, ed.)2nd edition, Vol. 1, pp. 329-350. Oxford University Press, N.Y.) andProceedings of the 10th Americal Peptide Symposium by Han et al. (in:Peptides, Chemistry and Biology, (G. R. Marshall, ed.), pp 581-583.Escom, Leiden). However, if such are used to treat other mammals, it maybe preferable to use EGF endogenous to the mammals, being treated.

The following may be the requirements on the topical acceptable carrierused in the invention:

-   -   1. non-toxic; and    -   2. the EGF will remain stable and bio-available when applied        directly to the skin wound.

The EGF can be dissolved in a liquid, dispersed or emulsified in amedium in a conventional manner to form a liquid preparation or is mixedwith a semi-solid (gel) or solid carrier to form a paste, powder,ointment, cream, lotion or the like for easy application to the skin.The choice of the final form may be decided in terms of convenience.

Although further description of the carrier may not be necessary to oneskilled in the art, some suitable carriers will now be listed. These mayinclude topically acceptable liquids, creams, oils, lotions, ointments,gels, or solids, such a conventional cosmetic night creams, foundationcreams, suntan lotions, sunscreens, hand lotions, make-up and make-upbases, masks and the like. The compositions can contain other optionalsuitable ingredients estrogen Vitamin A, C and E, alpha-hydroxy ofalpha-keto acids such as pyruvic, lactic or glycolic acids, lanolin,vaseline, aloe vera, methyl or propyl paraben, pigments and the like.Suitable topically acceptable carriers include water, petroleum jelly(vaseline), petrolatum, mineral oil, vegetable oil, animal oil, organicand inorganic waxes, such as microcrystalline, paraffin and ozoceritewax, natural polymers, such as xanthanes, gelatin, cellulose, collagen,starch, or gum arabic, synthetic polymers, such as discussed below,alcohols, polyols, and the like. Preferably, the carrier is a watermiscible carrier composition that is substantially miscible in water.Such water miscible topical cosmetically acceptable carrier compositioncan include those made with one or more appropriate ingredients setforth above but can also include sustained or delayed release carrier,including water containing, water dispersable or water solublecompositions, such as liposomes, microsponges, microspheres ormicrocapsules, aqueous base ointments, water-in-oil or oil-in-wateremulsions, gels or the like.

EXAMPLES

This invention is now illustrated by the following examples, which shallnot be interpreted as limiting.

Example 1 Group Study of Diabetes Foot Ulcer

Methods and Patients

A randomized double-blind controlled trial was conducted to study theefficacy of human epidermal growth factor hEGF) in promoting diabeticfoot ulcer healing with 88 patients. Predetermined criteria were usedfor patient selection, they were; ulcer grade 1-2, ulcer located belowthe ankle, adequate perfusion as indicated by an ankle brachial-index of≧0.7. Patients were excluded if: sugar control was very poor(HbAlc≧12%), or had severe grade ulcers (≧3). Initial assessment andstandard wound care and debridement was given as in an ordinary diabeticfoot clinic. The patients were reviewed two weeks later. In the secondconsultation, patients whose ulcer healed more than 25% withconventional foot ulcer care were excluded. Informed consent wasobtained from the remaining patients and randomization was done bydrawing envelopes, although the patients were blind to theconcentrations of hEGF during the experiments. The final candidates wererandomly assigned into three groups:

-   -   1. Group 1 were treated with Acetovegin® 5% cream alone, which        has the following compositions as indicated in the package of        the cream: 1 g of cream contains 2 mg (corresponding to dry        mass) of deproteinized hemoderivative of calf blood, and 0.2 mg        of benzalkonium chloride. There was no particular reason in        choosing Acetovegin® 5% cream as the control other than this        cream was available at the clinic where the experiments were        conducted.    -   2. Group 2 patients were treated with Acetovegin® 5% cream (with        composition as stated above) plus 0.02% (g/g) hEGF.    -   3. Group 3 patients were treated with Acetovegin® 5% cream (with        composition as stated above) plus 0.04% (g/g) hEGF.

All patients were followed up on a biweekly bass for wound care anddebridement and trimming of keratosis. Antibiotic would be given if itwas infected as indicated by purulent discharge or by positive bacterialculture. Photos of the wound's size were being taken for computermeasurement and comparing with a reference area having a known size.

Local application of study cream was applied and covered with sterilegauze. Patients were instructed to have daily normal saline dressing andlocal application of cream in the government out-patient-clinic orcommunity nurse would be asked to have home visit for those withambulatory problem.

Wound parameters, such as exudates sign of infection granulation tissueand eschar were documented in each visit and complete healing wasdefined as full epithelialization of the wound with absence ofdischarge.

Statistical Analysis

Analysis was based on intention to treat and Kaplan Meier survivalanalysis was employed to compare the healing rate between differentgroups. One way ANOVA was used for clinical parameters analysis. If morethan one wound was present in one patient the total areas of the ulcerswas taken together and treated as one single wound.

Results:

Among the 88 patients admitted to the experiments, 56 patients wereexcluded for various reasons: 23 (41%) because their ulcers healed morethan 25% in the second visit with conventional treatments. 19 (33.9%)had ankle-brachial-index; <0.7, 5 (8.9%) had high grade foot ulcer; 5(8.9%) refused because of social reason; 2 (3.6%) had poor diabetescontrol; another 2(3.9%) had ulcer above malleoli.

Of the 30 patients that suffered from unhealed ulcers they were randomlyassigned into 3 groups as stated above: Group-1 (9/30), the control, wastreated with Acetovegin® 5% cream alone; Group-2,(9/30) was treated withAcetovegin® 5% cream plus 0.02% (g/g) hEGF; Group-3, (14/32) Acetovegin®5% cream plus 0.04% (g/g) hEGF. The end point of a treatment was definedas complete closure of the wound, whereas failure to heal was defined asincomplete healing after 12 weeks of treatment.

Upon subsequent follow up, one patient from Group-1 was excluded beforecompletion of study because of relapse of a pysehictric symptom and poorcompliance (She had four ulcers over dorsum of her feet. Two of theulcers healed before she was excluded). One patient from Group-3 wasexcluded because of poor personal hygiene (she had five ulcers overdorsum and sole of her feet. Four of the ulcers healed before she wasexcluded at week-8). Final analysis consisted of 28 patients with 37ulcers. The baseline characteristics were depicted in Table 1. Therewere more female patients in Group-3. Other clinical parameters were ofno statistical difference among the groups. By the end of 12 weeks, fourpatients from Group-1, five patients from Group-2 and all patients fromGroup-3 healed with a healing rate 57%, 55% and 100%, respectively.

FIG. 1 shows the mean 100% healing times in Group 1, Group 2 and Group 3patients were 9.79±1.24 weeks (confidence interval (C.I.) 7.35-12.21),9.43±1.38 weeks (C.I. 6.73-12.13) and 6.67±0.93 weeks (C.I.4.84-8.49),respectively. Test statistics for equality of survival distributions(log rank) is 9.00 with a df of 2 and a significance of 0.0111. Furtherstatistical data of FIG. 1 is shown in Table 2. It can be observed thatGroup 3 patients took at least an average of 3 weeks less than the othertwo groups to heal and this difference was statistically significant.

FIG. 2 shows the mean 50% healing times in Group 1, Group 2 and Group 3patients were 7.33±1.21 weeks (confidence interval (C.I.) 4.96-9.71),5.71±1.02 weeks (C.I. 3.72-7.71) and 4.50±0.82 weeks (C.I.2.89-6.11),respectively. Test statistics for equality of survival distributions(log rank) is 4.25 with a df of 1 and a significance of 0.0392. Furtherstatistical data of FIG. 2 is shown in Table 3. It was shown that therewas a trend showing that the time required for an ulcer to reduce insize by 50% was also reduced in Group-3 and Group-2 treated with hEGF,as shown in FIG. 2.

TABLE 1 Baseline characteristics Group-1 Group-2 Group-3 Number 7 9 12 Sex (M/F) 3/4 4/5 2/10 Age (year)^(‡)  70 ± 5.6 66.28 ± 13.04 57.42 ±13.58 Ankle Brachial Index 1.03 ± 0.22 0.99 ± 0.16 1.05 ± 0.19 vibrationthreshold <25 (n) 5 3 7 >25 2 6 5 Wound area cm²# 2.78 ± 82   3.48 ±0.82 3.40 ± 1.1  Duration of  7.0 ± 5.48 12.78 ± 18.9  13.83 ± 16.59wound(week) Glycosylated  9.5 ± 1.78 8.89 ± 2.05 9.12 ± 1.06 Hemoglobin% ° Confidence level P = 0.052 # Confidence level P = 1

TABLE 2 Survival Analyis for 100% Healed Time (Weeks) of FIG. 1 (Mediansof Groups 1 and 2 are limited to 12 weeks) Survival Standard 95%Confidence Time Error Interval Group-1 Mean 9.78 1.24 7.35 12.21 Median12.00 2.98 6.16 17.84 Group-2 Mean 9.43 1.38 6.73 12.13 Median 12.005.24 1.74 22.26 Group-3 Mean 6.67 0.93 4.84 8.49 Median 6.00 1.71 2.659.35

TABLE 3 Survival Analysis for 50% Healed Time (Weeks) of FIG. 2 (Mediansof Groups 1 and 2 are limited to 12 weeks) Survival Standard 95%Confidence Time Error Interval Group-1 Mean 7.33 1.21 4.96 9.71 Median8.00 1.41 5.23 10.77 Group-2 Mean 5.71 1.02 3.72 7.71 Median 6.00 1.203.66 8.34 Group-3 Mean 4.50 0.82 2.89 6.11 Median 4.00 1.09 1.87 6.13

CONCLUSIONS

The data from the above studies revealed that a concentration of 0.04%(g/g) hEGF showed a significant healing effect in the treatment ofdiabetic foot ulcer. The average healing time for patents treated withthis concentration of hEGF is about 6 weeks, which is at least 3 weeksand significantly shorter than that treated with cream base alone andthat treated with 0.02% (g/g) hEGF. On the other hand, samplescontaining hEGF, whether in a concentration of 0.02% (g/g) or 0.04%(g/g), were shown to be able to expedite the healing process of diabetesfoot ulcers as judged by a reduced time to attain a reduced wound sizeby 50%.

Example 2 Individuals Suffering from Diabetes Ulcers

Three patients suffering from prolonged diabetes ulcers were treatedwith the composition of this invention containing 0.04% (g/g) hEGF. Thefollowing results were observed, with all of the patients were healedafter as short as four weeks treatment:

I. Patient A

Patient A, a 72-year old lady, suffered from type 2 diabetes (grade 1)for three years. Eye complication and normal vibration threshold testalso presented on oral medication.

Description of FIGURE FIG. Ulcer Area (cm²) Healing Rate (%) Beforetreatment 3 1.60 — After 2 weeks treatmeat 4 1.02 36.25 After 3 weekstreatment 5 0 100II. Patient B

Patient B, a 68-year old lady, suffered from type 2 diabetes (grade 1)for a 8 years. Both eye and kidney complication, and borderlinevibration threshold test presented.

Description of FIGURE FIG. Ulcer Area (cm²) Healing Rate (%) Beforetreatment 6 6.67 — After 3 weeks treatment 7 3.79 43.18 After 5 weekstreatment 8 1.62 75.71 After 9 weeks treatment 9 0.16 97.60I. Patient C

Patient C, a 46-year old lady, suffered form type 2 diabetes (grade 1)with no major complication.

Description of FIGURE FIG. Ulcer Area (cm²) Healing Rate (%) Beforetreatment 10 13.23 — After 4 weeks treatment 11 1.41 89.34 After 6 weekstreatment 12 0 100

Example 3 Individual Suffering from Prolonged Unhealed Surgical Wound

Patient D, aged 50, was admitted for investigation of right facialnon-healing ulcer after extraction of right mandibular molars andexcision of facial fistula eleven months ago. The facial ulcerationincreased in and with tendency of superior erosion. There was sloughingof the right mandibular alveolus and the wound was tender.

Blood tests, histopathology and microbiology revealed no specific causefor the non-healing wound. Repeated biopsy and microbiologicalinvestigations revealed no specific diagnosis. However, “definitivelynegative finding for malignancy nor basal cell carcinoma, quite normallooking oral epithelial mucosa” was reported by a pathologist.Computerized tommogram scanning of the face revealed a right facialulcer deep to the facial muscle with no bony lesion. A bone scan donerevealed hot uptake of the whole mandible.

Patient was reviewed after two weeks of hEGF (0.04% (g/g)) localapplication. The composition is the same as that used in the aboveGroup-3 patients. The right facial wound was healing, base of the woundlooked fleshy with no discharge. The wound area decreased in size byabout 30%. Further reduction in size was noted in subsequent follow up.The progress can be seen in FIGS. 13-15, in which FIG. 13 shows thephoto of the wound of Patient A before treatment; FIG. 14 shows thephoto of the wound of Patient A 2 weeks after being treated with thecomposition of this invention having 0.04% (g/g) of EGF; and FIG. 15shows the photo of the wound of Patient A 5 weeks after being treatedwith the composition of this invention having 0.04% (g/g) of EGF.

In conclusion, after 5 weeks of 0.04% of epidermal growth factor (hEGF)applied locally the refractroy facial wound achieved a approximately 50%reduction in size and decrease in wound depth.

Example 4 Individuals Suffering from Bedsore

Patient E, aged 82, was bedridden at aged home for several years. Shewas found to have pemphoid because of generalized blister eruptions andhas been on tailing dose of prednisone for more than 8 months. She wasreferred to medical because the wound got worse with central grangreneafter a two-month treatment.

She was then treated with Hibitane dressing for two weeks then normalsaline dressing with the composition of this invention containing 0.04%(g/g) EGF daily. Her wound was healed and completely closed afterthree-month treatment.

Description of FIGURE FIG. Before treatment 16 After 5 weeks treatment17 After 9 weeks treatment 18

Example 5 Results of 0.03% a (g/g) EGF

The experiment in Example 1 was repeated using Acetovegin® 5% cream plus0.03% (g/g) hEGF. 8 patients, named Group-4, were treated. The resultsare shown as follows:

Time Cumulative Standard Cumulative Number (weeks) Status Survival ErrorEvents Remaining 2 heal 0.8750 0.1169 1 7 4 heal 2 6 4 heal 0.62500.1712 3 5 6 heal 0.5000 0.1768 4 4 8 heal 0.3750 0.1712 5 3 10  heal0.2500 0.1531 6 2 12  heal 0.1250 0.1169 7 1 12  not heal 7 0 Number ofCases: 8 Censored: 1 (12.50%) Events: 7 95% Confidence Survival TimeStandard Error Level Mean 7 1 (5, 10) (Limited to 12) Median 6 3 (0, 12)

FIG. 19 shows the mean 100% healing times in Group 1, Group 2 (fromresults in Example 1 above) and Group-4 patients were 9.79±1.24 weeks(confidence interval (C.I.) 7.35-12.21), 9.43±1.38 weeks (C.I.6.73-12.13) and 7 weeks (C.I.5-10), respectively. Test statistics forequality of survival distributions (log rank) is 6.79 with a df of 2 anda significance of 0.0366. It can be observed that Group-4 patientstreated with 0.03% (g/g) (7 weeks) EGF healed almost as fat as thosetread with 0.04% (g/g) EGF (6.67 weeks) with no substantial statisticaldifference.

It can be seen that this invention may have provided a relativelyeffective treatment to serious, prolonged and unhealed skin wounds fromthe above examples. Such skin wounds can result from diabetes footulcers, bedsores, or surgical wounds. At the very least, this inventionmay have provided a solution to such skin wounds that traditionaltreatment methods may fail to heal. Further, the period required fortotal healing can be relatively short, and only 2-4 weeks may berequired in some cases, while other more severe wounds may require up to8 weeks.

While the preferred embodiment of the present invention has beendescribed in detail by the examples, it is apparent that modificationsand adaptations of the present invention will occur to those skilled inthe art. It is to be expressly understood, however, that suchmodifications and adaptations are within the scope of the presentinvention, as set forth in the following claim. Furthermore, theembodiments of the present invention shall not be interpreted to berestricted by the examples or figures only.

1. A method for treating a diabetic foot ulcer or bedsore woundcomprising the steps of: performing debridement to the skin wound; andtopically applying a composition to the skin wound, wherein saidcomposition comprises a topically acceptable carrier and at least 0.03%by weight of epidermal growth factor (EGF) wherein said EGF is effectiveat treating the wound.
 2. The method of claim 1, wherein the EGF is ahuman epidermal growth factor (hEGF).
 3. The method of claim 1, whereina topically effective amount of EGF is at least 0.04% by weight.
 4. Themethod of claim 1, wherein the EGF is a human epidermal growth factor(hEGF) and the composition comprises 0.03% to 0.04% by weight of hEGF.5. The method of claim 1 further comprising the steps of: (a) topicallyadministering said composition including 0.03% by weight of hEGF to theskin wound until area of the skin wound is reduced by 50%; and (b)topically administering said composition including 0.04% by weight hEGFto the skin wound after area of the skin wound is reduced by 50% untilthe skin wound is totally healed.
 6. The method of claim 1, wherein thetopically acceptable carrier is a water-miscible carrier.
 7. The methodof claim 1, wherein the topically acceptable carrier includes aconstituent selected from the group consisting of water, petroleumjelly, petrolatum, mineral oil, vegetable oil, animal oil, wax, and apolymer.